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Nucleotide Chemistry - Basics

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Publicada em

Dr. P. Harsha vardhan
Assistant Professor
Dpt of Biochemistry
Mallareddy Medical College for Women
Hyderabad, Telangana

Publicada em: Saúde e medicina
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Nucleotide Chemistry - Basics

  1. 1. NUCLEIC ACID CHEMISTRY • Nucleic acid structure basics. • Basics about DNA. • How DNA is organized. • RNA in detail.
  2. 2. Why Nucleic acid chemistry ??
  3. 3. 1. Basic Nucleic acid structure 1.1 Nitrogenous base 1.2 Sugars 1.3 Nucleoside 2. Nucleotide 2.1Properties of nucleotide 2.2 Functions 2.3 Synthetic Nucleotide Analogs
  6. 6. 1.1 NITROGENOUS BASE - Aromatic heterocyclic compounds PURINE PYRIMIDINE
  7. 7. PURINES - Pyrimidine ring + Imidazole ring.
  8. 8. PYRIMIDINES – One of the 3 isomer forms of DIAZINE(C4H4N2).
  9. 9. Some properties of nitrogenous bases - Weak Bases: Purines and Pyrimidines with NH2 in their structure act as weak bases. - Planar character: facilitates the close association or stacking that stabilizes thew structure of nucleic acids. - Tautomerism
  10. 10. TAUTOMERISM • Heterocyclic rings of nitrogenous bases with oxo groups exhibit keto(Lactam) enol(lactim) Tautomerism.
  11. 11. PROPERTY PURINE PYRIMIDINE Numbering Counterclockwise Clockwise Melting and Boiling points Higher Lower Glycosidic linkage with the sugar N present on 9th position forms glycosidic linkage. N present on 1st position forms glycosidic linkage. Biosynthesis Cytoplasm Cytoplasm+Mitochondria End product of metabolism Uric acid CO2, NH3
  12. 12. MINOR/UNUSUAL BASES • DNA and RNA contain small quantities of Minor/modified bases also - Methylation - Hydroxymethylation - Glycosylation - Alteration of atoms.
  13. 13. • Modification of Adenine: N-methyladenine, N6N6- dimethyladenine • Modification of Guanine: 7-methylguanine • Modification of Cytosine: 5-methylcytosine 5-hydroxymethylcytosine
  14. 14. • Modification of Uracil: Dihydroxyuracil • Special Bases: Hypoxanthine (6-oxopurine) Xanthine (2,6-dioxopurine) Uric acid (2,6,8-trioxopurine)
  15. 15. Purine bases of plants • Plants contain certain methylated purines. - Caffeine (1,3,7-trimethylxanthine): It is found in coffee, It acts as a stimulant of nervous system. - Theophylline (1,3-dimethylxanthine): Present in tea leaves. It acts as a bronchial smooth muscle relaxant.
  16. 16. 1.2 SUGARS - Ribose (in RNA) and Deoxyribose (in DNA). - Ribose and deoxyribose predominantly exist in the cyclic form.
  17. 17. 1.3 NUCLEOSIDE - Derivatives of sugar linked to ring Nitrogen of Purine or Pyrimidine . - Linkage is formed by -N-glycosidic bond. SUGAR  N9 of PURINE SUGAR  N1 of PYRIMIDINE
  18. 18. ADENOSINE
  19. 19. 2. NUCLEOTIDE • Mononucleotides are Nucleosides with a phosphoryl group esterified to a hydroxyl group of the sugar. • Additional phosphoryl groups, ligated by acid anhydride bonds to the phosphoryl group of a mononucleotide, form nucleoside diphosphates and triphosphates.
  20. 20. BASES NUCLEOSIDES NUCLEOTIDES Adenine (A) Adenosine Adenosine 5’-triphosphate (ATP) Deoxyadenosine Deoxyadenosine 5’-triphosphate (dATP) Guanine (G) Guanosine Guanosine 5’-triphosphate (GTP) Deoxyguanosine Deoxy-guanosine 5’-triphosphate (dGTP) Cytosine (C) Cytidine Cytidine 5’-triphosphate (CTP) Deoxycytidine Deoxy-cytidine 5’-triphosphate (dCTP) Uracil (U) Uridine Uridine 5’-triphosphate (UTP) Thymine (T) Thymidine/ Deoxythymidie Thymidine/deoxythymidie 5’-triphosphate (dTTP)
  21. 21. • Nucleoside bases common in DNA and RNA are highly conjugated molecules, a property with important consequences for the structure, electron distribution,and light absorption of nucleic acids. - Polyfunctional acids. - Absorption of UV light. - Syn and Anti Conformers. 2.1 PROPERTIES OF NUCLEOTIDES
  22. 22. 1. POLYFUNCTIONAL ACIDS • Phosphoryl groups of nucleosides have pKa values of 1.0, thus contribute to the negative charge at physiologic pH. • pKa values of the secondary phosphoryl groups are about 6.2 → proton donors or acceptors at pH values approximately 2 units ± NEUTRAL pH
  23. 23. 2. ABSORB U-V LIGHT • Conjugated double bonds of the purine and pyrimidine bases are characterized by a strong absorption at wavelengths near 260 nm at neutral pH. • Concentration is expressed as molar absorptivity at 260 nm. Importance: - Helps in identification of nucleic acids. -The mutagenic effect of ultraviolet light is due to its absorption by nucleotides in DNA that results in chemical modifications
  24. 24. 3. SYN AND ANTI CONFORMERS • Due to Steric hindrance by the heterocyclic ring there is no freedom of rotation about the -N-glycosidic bond. • Both therefore exist as non inter convertible Syn or Anti conformers . • Anti Conformers have more common occurrence • SYN & ANTI CONFORMERS interconversion - cleavage & reformation of the glycosidic bond.
  25. 25. i) Principal biologic transducer of free energy in metabolic inter conversions – ATP. ATP ADP + Pi - Group Transfer Potential: ATP acts a donor of phosphate group ATP + Creatinine Creatinine-P + ADP - Formation of a high energy intermediate: PPi – PYROPHOSPHATE. ATP AMP + PPi 2.2 NUCLEOTIDES – DIVERSE FUNCTIONS
  26. 26. ii) Allosteric regulation and energy source for protein synthesis. - GTP iii) Second messenger for Hormones: - c-AMP for Glucagon - c-GMP for Nitric oxide in smooth muscle relaxation
  27. 27. c-AMP c-GMP
  28. 28. iv) Carbohydrate metabolism: UDP-glucose and UDP- galactose participate in sugar inter conversions and in the biosynthesis of - Starch, glycogen - Glucosyl disaccharides, - Oligosaccharides of glycoproteins - Proteoglycans. UDP-Glucuronic acid forms the urinary glucuronide conjugates of bilirubin and of many drugs like aspirin
  29. 29. v) CTP participates in biosynthesis of: - Phosphoglycerides, - Sphingomyelin, - Substituted sphingosines. vi) Lipid metabolism: Nucleoside-lipid derivatives such as CDP-acyl glycerol are intermediates in lipid biosynthesis.
  30. 30. vii) Signal transduction pathways: - GTP and GDP play key roles in signal transduction pathways. viii) Coenzymes: - When linked to vitamins or vitamin derivatives function as coenzymes e.g: Niacin, Pyridoxine, Pantothenic acid derivatives, Coenzyme A.
  31. 31. ix) Donor of various groups: a) 3'Phosphoadenosine -5'-phosphosulfate - Sulphate donor for proteoglycans and sulfate conjugate of drugs. .
  32. 32. b) S-adenosylmethionine - Methyl donor in various metabolic reactions in Liver
  33. 33. 2.3 SYNTHETIC NUCLEOTIDE ANALOGS • Modifications in Heterocyclic ring or in the Sugar moiety  SYNTHETIC ANALOG. Incorporation into nucleic acids with resulting disruption of base-pairing Inhibition of enzymes essential for nucleic - acid synthesis
  34. 34. 1) Cancer chemotherapy: Incorporated into DNA prior to cell division. 5-fluoro- or 5-iodouracil, 5-iodo-2’-deoxyuridine, 6-mercaptopurine, 6-thioguanine 6-azauridine,8-azaguanine, Cytarabine etc. APPLICATIONS OF SYNTHETIC ANALOGS
  35. 35. 2) Suppresion of Organ transplant rejection: - Azathioprine 3) Viral Diaseases: - Arabynosyladenoisine for Encephalitis. - Zidovudine for HIV infection.
  36. 36. 4) Metabolic diseases: Allopurinol - It is structurally similar to hypoxanthine, inhibits the enzyme activity of XANTHINE OXIDASE. - Used in treatment of hyper uricemia and gout.